Clinical and genetic characteristics of Dent's disease type 1 in Europe.

BACKGROUND: Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis-nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. METHODS: A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. RESULTS: A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. CONCLUSIONS: Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.

Treatment and long-term outcome in primary nephrogenic diabetes insipidus.

BACKGROUND: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome. METHODS: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form. RESULTS: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0-60) years and at last follow-up 14.0 (0.1-70) years. In adults, height was normal with a mean (standard deviation) score of -0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients. CONCLUSION: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems.

Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome.

Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and general edema. These symptoms may persist in children who reach ESRD, which is unfavorable for the patient's allograft outcome. In addition, this may hamper early diagnosis of a relapse after transplantation. Surgical bilateral nephrectomy is often considered for that reason, but medical nephrectomy may be a less invasive alternative. In this retrospective single-center case series, we identified all children on dialysis with ESRD due to nephrotic syndrome in which a medical nephrectomy was attempted before kidney transplantation between 2013 and 2018. Outcome was measured by urine output and serum albumin levels. Eight patients with either congenital nephrotic syndrome or focal segmental glomerular sclerosis were included in the study. All patients received an ACE inhibitor as drug of first choice for medical nephrectomy, to which 5 patients responded with oligoanuria and a significant rise in serum albumin, and 3 patients responded insufficiently. In 1 of these 3 patients, diclofenac was added to the ACE inhibitor, with good result. In the other 2 patients, indomethacin was initiated without success, and surgical bilateral nephrectomy was performed. Overall, 6/8 patients had a successful medical nephrectomy and did not need surgical nephrectomy. No recurrence of nephrotic syndrome was found after kidney transplantation in all but one. Medical nephrectomy with ACE inhibitors and/or non-steroidal anti-inflammatory drugs is a safe and non-invasive therapy to minimize proteinuria in children with ESRD due to nephrotic syndrome before kidney transplantation. We suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy.

Association between timing of dialysis initiation and clinical outcomes in the paediatric population: an ESPN/ERA-EDTA registry study.

BACKGROUND: There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment. METHODS: We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ≥8 mL/min/1.73 m2 (early starters) and eGFR <8 mL/min/1.73 m2 (late starters). The primary outcomes were patient survival and access to transplantation. Secondary outcomes were growth and cardiovascular risk factors. Sensitivity analyses were performed to account for selection- and lead time-bias. RESULTS: The median eGFR at the start of dialysis was 6.1 for late versus 10.5 mL/min/1.73 m2 for early starters. Early starters were older [median: 11.0, interquartile range (IQR): 5.7-14.5 versus 9.4, IQR: 2.6-14.1 years]. There were no differences observed between the two groups in mortality and access to transplantation at 1, 2 and 5 years of follow-up. One-year evolution of height standard deviation scores was similar among the groups, whereas hypertension was more prevalent among late initiators. Sensitivity analyses resulted in similar findings. CONCLUSIONS: We found no evidence for a clinically relevant benefit of early start of dialysis in children with ESKD. Presence of cardiovascular risk factors, such as high blood pressure, should be taken into account when deciding to initiate or postpone dialysis in children with ESKD, as this affects the survival.

Treatment and long-term outcome in primary distal renal tubular acidosis.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. METHODS: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. RESULTS: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. CONCLUSION: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

Hemodialysis vascular access and subsequent transplantation: a report from the ESPN/ERA-EDTA Registry.

BACKGROUND: Current guidelines advocate use of arteriovenous fistula (AVF) over central venous catheter (CVC) for children starting hemodialysis (HD). European data on current practice, determinants of access choice and switches, patient survival, and access to transplantation are limited. METHODS: We included incident patients from 18 European countries who started HD from 2000 to 2013 for whom vascular access type was reported to the ESPN/ERA-EDTA Registry. Data were evaluated using descriptive statistics, logistic and Cox regression models, and cumulative incidence competing risk analysis. RESULTS: Three hundred ninety-three (55.1%) of 713 children started HD with a CVC and were more often females, younger, had more often an unknown diagnosis, glomerulonephritis, or vasculitis, and lower hemoglobin and height-SDS at HD initiation. AVF patients were 91% less likely to switch to a second access, and two-year patient survival was 99.6% (CVC, 97.2%). Children who started with an AVF were less likely to receive a living donor transplant (adjusted HR, 0.30; 95% CI, 0.16-0.54) and more likely to receive a deceased donor transplant (adjusted HR, 1.50; 95% CI, 1.17-1.93), even after excluding patients who died or were transplanted in the first 6 months. CONCLUSIONS: CVC remains the most frequent type of vascular access in European children commencing HD. Our results suggest that the choice for CVC is influenced by the time of referral, rapid onset of end-stage renal disease, young age, and an expected short time to transplantation. The role of vascular access type on the pattern between living and deceased donation in subsequent transplantation requires further study.

Children on dialysis as well as renal transplanted children report severely impaired health-related quality of life.

OBJECTIVES: To assess health-related quality of life (HRQoL) across three renal replacement therapy modalities (preemptive transplant, non-preemptive transplant, and dialysis) in comparison with the healthy norm and other chronic health conditions, and to explore related patient factors. STUDY DESIGN: All prevalent end-stage renal disease (ESRD) patients aged 8-18 years who spent at least 6 months on their current treatment modality in the Netherlands, Belgium, and part of Germany were approached to complete the Pediatric Quality of Life Inventory 4.0 (PedsQL™) questionnaire. We determined the differences between groups on PedsQL™ mean scores, the proportion of children with an impaired HRQoL (≥ 1 SD lower than the healthy norm), the proportion of problems on individual items of the PedsQL™, and the effect of time on current treatment. Linear regression models were used to explore determinants of HRQoL. RESULTS: 192 out of 278 patients (20% preemptive transplant, 58% non-preemptive transplant, 22% dialysis) filled in the PedsQL™ (response rate 69%). Independent of treatment modality, patients had significantly lower mean scores and consequently higher proportions of impaired HRQoL on almost all domains compared to the healthy norm and other chronic health conditions. Patients with a preemptive transplant only reported higher scores on physical health compared to the other treatment modalities. Having comorbidities was the most important determinant associated with lower HRQoL scores. CONCLUSION: Dialysis and renal transplantation both have a severe impact on the HRQoL of children with ESRD. Physicians should be aware of this continuous burden. Furthermore, to develop tailored interventions for children with ESRD, qualitative studies are needed to gain more insight in the determinants of HRQoL in the different treatment modalities.

AGORA, a data- and biobank for birth defects and childhood cancer.

BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.

Tubular Injury Biomarkers to Detect Gentamicin-Induced Acute Kidney Injury in the Neonatal Intensive Care Unit.

OBJECTIVE: We evaluated whether urinary excretion of tubular injury markers could be useful for early detection of gentamicin (GM)-induced renal damage in neonates. STUDY DESIGN: We conducted a prospective, observational trial in neonates admitted to the neonatal intensive care unit (26 GM treated, 20 control). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-D-glucosaminidase (NAG), and π- and α-glutathione-S-transferase (GSTP1-1 and GSTA1-1) were measured every 2 hours during admission and compared with serum creatinine (sCr) and urine output. RESULTS: Nine neonates developed AKI during the course of the study. The peak in excretion of urinary biomarkers preceded the peak in sCr (p < 0.0001). GM administration resulted in a more pronounced increase of sCr compared with control (13 [12-28] vs. 10 µmol/L [8.5-17]; p < 0.05). The urinary excretion of NAG (178 [104-698] vs. 32 ng/mol Cr [9-82]; p < 0.001) and NGAL (569 [168-1,681] vs. 222 ng/mol Cr [90-497]; p < 0.05) was higher in the GM group compared with control and preceded the peak of sCr and urine output decrease. CONCLUSION: GM administration to neonates is associated with renal damage reflected by a more pronounced increase in sCr preceded by urinary excretion of biomarkers. Urinary biomarkers may be useful for earlier identification of renal injury in neonates.

Children of non-Western origin with end-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health-related quality of life compared with Western children.

BACKGROUND: Many children with end-stage renal disease (ESRD) living in Western Europe are of non-Western European origin. They have unfavourable somatic outcomes compared with ESRD children of Western origin. In this study, we compared the Health-related Quality of Life (HRQoL) of both groups. METHODS: All children (5-18 years) with ESRD included in the RICH-Q project (Renal Insufficiency therapy in Children-Quality assessment and improvement) or their parents were asked to complete the generic version of the Paediatric Quality-of-Life Inventory 4.0 (PedsQL). RICH-Q comprises the Netherlands, Belgium and a part of Germany. Children were considered to be of non-Western origin if they or at least one parent was born outside Western-European countries. Impaired HRQoL for children with ESRD of Western or non-Western origin was defined as a PedsQL score less than fifth percentile for healthy Dutch children of Western or non-Western origin, respectively. RESULTS: Of the 259 eligible children, 230 agreed to participate. One hundred and seventy-four children responded (response rate 67%) and 55 (32%) were of non-Western origin. Overall, 31 (56%) of the ESRD children of non-Western origin, and 58 (49%) of Western origin had an impaired total HRQoL score. Total HRQoL scores of children with ESRD of Western origin and non-Western origin were comparable, but scores on emotional functioning and school functioning were lower in non-Western origin (P=0.004 and 0.01, respectively). The adjusted odds ratios (95% confidence interval) for ESRD children of non-Western origin to have impaired emotional functioning and school functioning, compared with Western origin, were 3.3(1.5-7.1) and 2.2(1.1-4.2), respectively. CONCLUSION: Children with ESRD of non-Western origin in three Western countries were found to be at risk for impaired HRQoL on emotional and school functioning. These children warrant special attention.

Policy variation in donor and recipient status in 11 pediatric renal transplantation centers.

BACKGROUND: Evidence-based guidelines for pediatric renal transplantation (Tx) are lacking. This may lead to unwanted treatment variations. We aimed to quantify the variation in treatment policies and its consequences in daily practice in 11 centers that provide renal Tx for children in three European countries. METHODS: We surveyed Tx policies in all ten centers in the Netherlands and Belgium and one center in Germany. We compared Tx policies with the therapies actually provided and with recommendations from available published guidelines and existing literature. Information on treatment policies was obtained by a questionnaire; information on care actually provided was registered prospectively from 2007 to 2011. The clinical guidelines were identified by searches of MEDLINE and websites of pediatric nephrology organizations. RESULTS: Between centers, we found discrepancies in policies on: the minimum accepted recipient weight (8-12 kg), the maximum living and deceased donor age (50-75 and 45-60 years, respectively). HLA-match policies varied between acceptation of all mismatches to at least 1A1B1DR match donor transplantations amounting to 49 % in the Netherlands versus 26 % in Belgium (p = 0.006). CONCLUSIONS: Management policies for renal Tx in children vary considerably between centers and nations. This has a direct impact on the delivered care, and by extrapolation, on health outcome.

The strengths and complexities of European registries concerning paediatric kidney transplantation health care.

Introduction: Patient data are increasingly available in (multi)national registries, especially for rare diseases. This study aims to provide an overview of current European registries of paediatric kidney transplantation (PKT) care, their coverage, and their focus. Based on these data, we assess whether the current status is optimal for achieving our common goal: the optimalisation of health care. Methods: A list of all PKT centres within the European Union (EU) as well as active PKT registries was compiled using existing literature and the European Platform on Rare Disease Registration. Registry staff members were contacted to obtain information about the parameters collected and the registry design. These data were compared between registries. Results: In total, 109 PKT centres performing PKT surgery were identified in the 27 EU Member States. Currently, five European PKT registries are actively collecting data. In 39% of these centres, no data were registered within any of these five existing international registries. A large variety was observed in the number of patients, centres, and countries involved in the registries. Furthermore, variability existed regarding the inclusion criteria, definitions used, and parameters collected. Collection of perioperative urologic data are currently underrepresented in the registries. Discussion: Currently, multiple registries are collecting valuable information in the field of PKT, covering the majority of PKT centres in Europe. Due to a large variety in the parameters collected as well as different focuses, data collection is currently fragmented and suboptimal; therefore, the current existing data are incomplete. In addition, a considerable proportion of the transplantation centres do not enter data in any international registry. Combining available information and harmonising future data collection could empower the aim of these registries-namely increasing insights into the strengths and potential of current care and therefore improve healthcare.

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study.

BACKGROUND: The low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children. METHODS: We surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010. RESULTS: Data on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available. CONCLUSIONS: Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking.

Fewer pre-emptive renal transplantations and more rejections in immigrant children compared to native Dutch and Belgian children.

BACKGROUND: In the Netherlands and Belgium, an increasing number of children who have end-stage renal disease (ESRD) are of non-Western origin. We analysed renal transplantation practices and outcome for immigrant ESRD children as compared to native children in both countries. METHODS: All Dutch and Belgian children aged <19 years who received their first renal transplantation between 1 September 2007 and 1 January 2011 were included. Therapy characteristics and outcomes were registered prospectively on a 3-monthly basis. Immigrants were defined as children of whom one or both parents had been born outside Western European countries. Multivariable Cox regression analysis was used to quantify the hazard ratio for acute rejection. RESULTS: One hundred and nineteen first renal transplant recipients were included, of which 41 (34%) were immigrants. Median [range] follow-up time of transplantation was 18 [2-28] months. Compared to native children, immigrants had pre-emptive transplantations (15 versus 32%, P = 0.040) and transplantations with a kidney from a living donor less often (24 versus 59%, P < 0.001). Survival analysis in 96 children with at least 3 months of follow-up showed an increased risk for acute rejection in immigrants adjusted for donor source, duration of dialysis and number of HLA mismatches on the DR locus [hazard ratio (95% confidence interval) 2.5 (1.1-5.9)]. CONCLUSIONS: Immigrant children receive fewer pre-emptive and living donor transplantations compared to native children. After transplantation, immigrant children are at higher risk for acute rejection irrespective of the mode of transplantation.

Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents.

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy.

Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell's signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician's ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals.